The world's population is aging rapidly, and the number of people over 60 years of age will rise to 2 billion in 2050. As a result, age-related cognitive decline is becoming a pressing social and health concern. Physiologically, damage to the structures of the medial temporal lobe including the hippocampus, contributing to the decreased spatial memory often associated with aging, represents one research focus in this regard (Barnes 1988; von Bohlen and Halbach et al 2006). Biochemically, oxidative damage by reactive oxygen species (ROS) has been implicated in normal aging (Finkel and Holbrook 2000; Barja 2004). There is in the human body also a balance between pro-inflammatory agents such as interleukin-6 (IL-6), C-reactive protein and tumor necrosis factor-alpha (TNF-alpha), which can confer high resistance to infectious diseases but also increased susceptibility to inflammation-based diseases later in life, and anti-inflammatory agents such as TNF-beta and IL-10. In old age, the balance is shifted to the pro-inflammatory agents, resulting in a chronic low-grade inflammation referred to as ‘inflammaging’, which is accompanied by elevated pro-inflammatory cytokines, and represents a highly significant factor for both morbidity and mortality (Franceschi et al 2007; Franceschi and Campisi 2014). Long-lived people, especially centenarians, seem to cope with inflammaging through an “anti-inflammaging” cytokine response, and it is suggested that anti-inflammaging may be a key to longevity (Minciullo et al 2016). Therefore treatments that can alleviate spatial memory deficit, relieve oxidative stress and/or lower elevated levels of pro-inflammatory agents such as TNF-alpha and IL-6 are important for reducing the effect of aging.
The health problems of normal aging overlap with those posed by age-related degenerative diseases. Thus memory loss is the key affliction in Alzheimer's disease (“AD”) (Wolbers et al 2014; Tanila 2012). Oxidative stress is important to both Alzheimer's disease and Parkinson's disease (Lovell et al 1995; Nunomura et al 2001; Perry et al 2002; Henchcliffe and Beal 2008), and antioxidants have been proposed for the prevention and treatment of neurodegenerative disorders including both Alzheimer's disease and Parkinson's disease (Prasad et al 1999; Moosmann and Behl 2002; Fernandez-Checa et al 2010). In addition, AD is associated with the occurrence of amyloid plaques, tau-protein abnormalities and neuroinflammation, and it has been suggested that neuroinflammation is not a passive system activated by emerging senile plaques and neurofibriller tangles, but contributes as much or more to pathogenesis as do plaques and tangles themselves (Heneka et al 2015). When 56 patients with mild cognitive impairment (MCI) were monitored prospectively for nine months, 25 patients remained at the MCI stage while the other 31 patients had progressed to AD. Only the latter group showed significantly higher cerebralspinal fluid levels of TNF-alpha than controls, indicating that CNS inflammation is an early hallmark in AD pathogenesis (Tarkowski et al 2003). Cytokine expression profiles in the brain of two transgenic mouse models of AD, viz. TgAPPsw and PS1/APPsw, also confirmed that these brains are under active inflammatory stress with major enhancement of TNF-alpha, IL-6, IL1-alpha and GM-CSF in the brain slices (Patel et al 2005). Trials to date of anti-inflammatory prevention of AD with aspirin, steroidal and non-steroidal anti-inflammatory drugs have yielded disappointing results (Jaturapatpom et al 2012; Alzheimer's Disease Anti-inflammatory Prevention Trial Reseach Group 2013) despite earlier, more positive outcomes (Breitner 2011). However, the non-steroidal anti-inflammation drug (NSAID)-derived CHF5074 reduced the concentrations of the neuroinflammation biomarkers TNF-alpha and sCD40L in the cerebrospinal fluid of patients with mild cognitive impairment (Ross et al 2016). Such modulation of neuroinflammation markers supports the suggestion that combination therapy consisting of a drug targeting the amyloid-beta (Aβ) and/or tau protein, and a medication modulating neuroinflammation may provide a way to substantially delay the progression of AD (Heppner et al 2015). Therefore, agents that can lower oxidative stress can be useful for the prevention and/or treatment of Alzheimer's disease and Parkinson's disease, and agents that can diminish spatial memory deficit and/or lower brain levels of pro-inflammatory agents such as TNF-alpha or IL-6 provide drugs for Alzheimer's disease.
The health problems arising from spatial memory deficit, oxidative stress, inflammation, anxiety and sleep disorders, which can impinge on the brain and are common among old people, require preventive and/or therapeutic agents that are relatively free of adverse side effects so that they can be administered on a chronic basis, and capable of crossing the blood-brain barrier so that they can be effective on all organs in the body including the brain. In this regard, a large number of Chinese medicinal herbs have been employed for medicinal purposes over centuries and are known to be suitable for chronic use. Previously, a search for an anxiolytic herbal decoction has led to the development of the Erhuhuanteng, or “BYPA”, decoction (Xue and Wong 2008) containing the four Chinese medicinal herbs Radix Bupleurum chinense DC (“B”), Rhizoma Corydalis yanhusuo WT Wang (“Y”), Caulis Polygonum multiflorum Thunb (“P”) and Flos Albizia julibrissin Durazz (“A”), which has been subjected to acute and chronic toxicity testing and approved for marketing as the anxiolytic Calmlin™ decoction by the Department of Health of Hong Kong SAR. As an anxiolytic decoction, it also may be expected to contain ingredients that can cross the blood-brain barrier. Some general uses (Xie and Huang 1991) and known findings of these four medicinal herbs include:
Radix Bupleurum chinense DC is employed as an antipyretic for intermittent fever, for relief of pains in the sides and chest, and to enhance the vitality of the spleen. It also reduces total cholesterol and triglycerides, increases the levels of low-density lipoprotein cholesterol in blood (Shao et al, 2002) and exhibits affinity for a range of receptors including dopamine D1 and D2, muscarinic acetylcholine M1, 5-HT1 and 5-HT2, and GABAA receptors (Liao et al., 1995).
Rhizoma Corydalis yanhusuo WT Wang, has been employed frequently for treatment of all kinds of pain in the chest and abdomen, elevating the threshold of pain and relieving spastic pain. It is also used with other herbs such as Angelicae dahuricae for relief of pain (Yuan et al., 2004). It contains dl-tetrahydropalmatine which induces anxiolytic effects in mice when administered orally (Leung et al., 2003). The l-tetrahydropalmatine isomer is a dopamine receptor antagonist (Xu et al, 1989; Mantsch et al, 2007), attenuates oxycodone-induced conditioned place preference (Liu et al 2009) and heroine self-administration (Yue et al 2012), and is approved in China as an analgesic in the form of ‘Rotundine’ tablets and injection (Chinese Pharmacopoeia Committee (2015).
CaulisPolygonum multiflorum Thunb is employed as a sedative for neurasthenia, insomnia and dreamfulness, and to activate blood circulation in collaterals for treatment of aching limbs. It can induce synergistic hypnotic effects when co-administered with pentobarbital (Wing, 2001).
Flos Albizia julibrissin Durazz is employed as sedative and tranquilizer for the treatment of fidgetiness and insomnia. It is known to increase pentobarbital-induced sleeping time in a dose dependent manner (Ji et al., 2007; Kang et al., 2000), and exhibit anti-depressant-like effect in the forced swim test (Li et al., 2006).